Understanding the Different Microglia Functional States to Modulate Their Activity in Retinal Degeneration.

Recent advances in genomic, transcriptomic, and imaging have advanced our understanding of microglia cells and their role in neurodegenerative diseases. These dynamic cells can change into distinct functional subpopulations with unique genetic markers and specialized functions once they migrate to the injury site. The model illustrated in Fig. 23.1 predicts that once the tissue recovers from the injury, the predominant microglia functional state should be the homeostatic state and localize within the retina's inner plexiform layers. However, microglia cells do not return to the predominantly homeostatic functional state during retinal degeneration (von Bernhardi et al., Front Aging Neurosci 7:124, 2015). Studies in animal models suggest that during retinal degeneration, rather than maintaining the homeostatic state, microglia can become dysregulated and remain pro-inflammatory, thus exacerbating tissue damage (Rashid et al., Front Immunol 10:1975, 2019; Wang and Cepko, Front Immunol 13:843558, 2022). To address the increased inflammation and excessive phagocytosis seen in these models, some studies employed the use of genetic and pharmacological methods to deplete retinal microglia (Zhao et al., EMBO Mol Med 7:1179-1197, 2015; Wang et al., J Neurosci 36:2827-2842, 2016). Because of their multiple physiological functions, microglia depletion is not a feasible therapeutic approach to address neuroinflammation. Instead, manipulating microglia functions should take center stage when developing therapies for neuroinflammation. Thus, defining the genetic network that regulates microglia functional states is essential to developing therapies to modulate microglia.